Project Summary Cardiovascular (CV) disease and cancer are leading causes of morbidity and mortality in the US. Highly effective breast cancer therapies, such as doxorubicin and trastuzumab (Herceptin) are used widely and have led to important oncologic survival gains. However, these agents carry a significant risk of cardiovascular (CV) morbidity and mortality. Doxorubicin-induced CV dysfunction, as defined by left ventricular ejection fraction (LVEF) declines, occurs in 10-15% of patients at dosages of 240mg/m2. Doxorubicin and trastuzumab in combination result in LVEF declines in up to 33% of individuals, and severe, symptomatic heart failure (HF) in 2-4%. The development of LVEF declines and HF can result in treatment interruptions, worse oncologic outcomes, and worse overall survival. Our R21 application is directly responsive to NIH PA 19-111, and the critical need to understand which cancer patients are at increased cardiotoxicity (CTX) risk and to develop strategies to mitigate this risk. The prophylactic use of cardioprotective pharmacotherapies in all patients undergoing cancer therapy results in the unnecessary treatment of low-risk patients, and raises concerns over adherence, adverse effects, and tolerability. Risk scores, while widely used in cardiology and oncology, have not yet been applied to cardio- oncology. This R21 application leverages the critical insights gained in R01 HL118018, focused on defining individual patient risk and the functional and biologic perturbations secondary to cancer therapy in the Penn Cardiotoxicity of Cancer Therapy (Penn CCT) cohort study. We have developed and validated a simple, but robust risk score to predict CTX using readily obtained and easily accessible patient-level data at baseline. Prior to embarking on a large, multi-center clinical trial, we first need data to support the feasibility, safety, and potential efficacy of our approach. Thus, we propose a randomized, placebo controlled pilot study of carvedilol in high CV risk patients. We will apply our risk score to breast cancer patients prior to doxorubicin and/or trastuzumab therapy; identify patients with elevated baseline CV risk; and randomize high risk patients to carvedilol or placebo. Through this pilot study, we will gain insight into the following key questions: Is a risk guided strategy feasible? Is carvedilol well-tolerated and safe in patients undergoing breast cancer therapy? Does carvedilol attenuate the declines in LVEF observed in high CV risk patients? Our ultimate goals are to prevent cancer therapy cardiotoxicity through an innovative paradigm of cancer care delivery of targeted cardioprotection based upon individual patient risk.